Update on the Treatment of HCV

Transcription

1 Update on the Treatment of HCV K. Rajender Reddy, MD Professor of Medicine Director of Hepatology Director, Viral Hepatitis Center University of Pennsylvania Philadelphia, USA 1 K. Rajender Reddy, MD Disclosure Statement Consultant/Advisory Board: AbbVie Inc; Bristol-Myers Squibb; Genentech, Inc; Gilead Sciences, Inc; Janssen Pharmaceuticals, Inc; Merck & Co, Inc; Vertex Pharmaceuticals Investigator: AbbVie Inc; Bristol-Myers Squibb; Genentech, Inc; Gilead Sciences, Inc; Janssen Pharmaceuticals, Inc; Merck & Co, Inc; Vertex Pharmaceuticals (funds are paid to University of Pennsylvania) 1

2 HCV is a Viral Disease that Affects the Liver, with ~170M Infected Individuals Worldwide Epidemiology and distribution of HCV genotypes in the world Of the 170M HCV-infected, approximately 95 million live in the Asia-Pacific Region 4M 12M 5M 43M 2M 6 different HCV genotypes WW with genotypes 1, 2 and 3 comprising the majority of patients 7M Brazil Current DAA combinations primarily address genotype 1 Pan-genotypic treatments can be used widely in both developed and emerging countries - Roughly half of WW HCVinfected are non-gt1 Despite High Prevalence and Increasing Disease Burden, Most Americans With Chronic HCV Have Not Been Diagnosed and Few Have Been Treated 60% 50% 40% 30% Overall: 3.2 million of U.S. population with chronic HCV 50% (1.6M) 32-38% ( M) 20% 10% 7-11% (220, ,000) 000) 5-6% (170, ,000) 0% Diagnosed Referred to Care Treated Successfully Treated Holmberg SD et al. New Engl J Med. 2013;368:

3 Who Should Be Tested for HCV CDC Recommendations Everyone born from 1945 through 1965 (one-time) Persons who ever injected illegal l drugs Persons who received clotting factor concentrates produced before 1987 Chronic (long-term) hemodialysis Persons with persistently abnormal ALT levels Recipients of transfusions or organ transplants prior to 1992 Persons with recognized occupational exposures Children born to HCV-positive women HIV-positive persons USPSTF Grade B Recs* Everyone born from 1945 through 1965 (one-time) Past or present injection i drug use Sex with an IDU; other high-risk sex Blood transfusion prior to 1992 Persons with hemophilia Long-term hemodialysis Born to an HCV-infected mother Incarceration Intranasal drug use Receiving an unregulated tattoo Occupational percutaneous exposure Surgery before implementation of universal precautions *Only pertains to persons with normal liver enzymes; if elevated liver enzymes need HBV and HCV testing Smith BD et al. Ann Intern Med. 2012;157: (C) Moyer VA et al. Ann Intern Med Sep 3;159(5): (C) Direct Acting Antivirals Against HCV asvirs NS5A Inhibitors previrs Protease Inhibitors Nucs Non-Nucs Polymerase Inhibitors buvirs Manns, von Hahn, Nat Rev Drug Discov

4 Asunaprevir Danoprevir ABT-450/r MK-5172 Sovaprevir Direct Acting Antivirals Against HCV.. Daclatasvir Ledipasvir ABT-267 asvirs NS5A Inhibitors Simeprevir Faldaprevir Boceprevir Telaprevir previrs Protease Inhibitors ABT-333 ABT-072 Deleobuvir BMS Setrobuvir Filibuvir VX-222. Nucs Non-Nucs Polymerase Inhibitors buvirs Sofosbuvir Mericitabine ALS-2200 Manns, von Hahn, Nat Rev Drug Discov 2013 Regimen PEG + RBV Antiviral Therapies for Genotype 1 Currently Available PEG + RBV + boceprevir PEG + RBV + telaprevir PEG + RBV + simeprevir PEG + RBV + sofosbuvir RBV + sofosbuvir* (Extended duration) Sofosbuvir + simeprevir DAA Class None Protease inhibitor (PI) Protease inhibitor Protease inhibitor Nucleotide analogue NS5B polymerase inhibitor Nucleotide analogue NS5B polymerase inhibitor NUC + PI (off-label) *Sofosbuvir + ribavirin for 24 wks can be considered in patients with genotype 1 HCV who are ineligible for interferon. RBV, ribavirin AASLD/IDSA treatment recommendations. Accessed June 18,

5 TREATMENT OF CHRONIC HEPATITIS C: GENOTYPE 1 Treatment-Naïve and Prior Relapsers AASLD/IDSA/IAS-USA 2014 HCV Treatment Recommendations Initial Therapy for Patients with Genotype 1 Chronic HCV Patients with GT 1 HCV: Initial Treatment & Retreatment of Relapsers* Recommended Therapy Interferon Eligible Sofosbuvir + Peginterferon + Ribavirin x 12 weeks Not Interferon Eligible Sofosbuvir + Simeprevir +/- Ribavirin x 12 weeks *Patients who experienced relapse after Peginterferon plus Ribavirin therapy Source: AASLD/IDSA/IAS-USA ( Viewed April 22,

6 AASLD/IDSA/IAS-USA 2014 HCV Treatment Recommendations Initial Therapy for Patients with Genotype 1 Chronic HCV Patients with GT 1 HCV: Initial Treatment & Retreatment of Relapsers* Alternative Therapy Interferon Eligible ^Simeprevir x 12 weeks + [Peginterferon + Ribavirin] x 24 weeks Not Interferon Eligible + Sofosbuvir + Ribavirin x 24 weeks *Patients who experienced relapse after Peginterferon plus Ribavirin therapy ^Acceptable regimen for persons with genotype 1b or genotype 1a in whom Q80K polymorphism not detected prior to treatment + Preliminary data suggest this regimen may be less effective than sofosbuvir + simeprevir, particularly for patients with cirrhosis Source: AASLD/IDSA/IAS-USA ( Viewed April 22, 2014 TREATMENT OF CHRONIC HEPATITIS C: GENOTYPE 1 Retreatment of Prior Nonresponders 6

7 AASLD/IDSA/IAS-USA 2014 HCV Treatment Recommendations Retreatment of Patients with Genotype 1 Chronic HCV Patients with GT 1 HCV: Retreatment of Prior Nonresponders* Recommended Therapy Sofosbuvir + Simeprevir +/- Ribavirin x 12 weeks *Patients who experienced nonresponse (partial or null) with Peginterferon plus Ribavirin therapy Source: AASLD/IDSA/IAS-USA ( Viewed April 8, 2014 AASLD/IDSA/IAS-USA 2014 HCV Treatment Recommendations Retreatment of Patients with Genotype 1 Chronic HCV Patients with GT 1 HCV: Retreatment of Prior Nonresponders* Alternative Therapy Sofosbuvir x 12 weeks + [Peginterferon + Ribavirin] x weeks Sofosbuvir + Ribavirin x 24 weeks ^Simeprevir x 12 weeks + [Peginterferon + Ribavirin] x 48 weeks *Patients who experienced nonresponse (partial or null) with Peginterferon plus Ribavirin therapy ^For genotype 1a, baseline resistance testing for Q80K should be performed and alternative treatments considered if this mutation is present Source: AASLD/IDSA/IAS-USA ( Viewed April 8,

8 AASLD/IDSA/IAS-USA 2014 HCV Treatment Recommendations Retreatment of Patients with Genotype 1 Chronic HCV Patients with GT 1 HCV: Retreatment of Prior Nonresponders* Not Recommended Peginterferon + Ribavirin +/- [Boceprevir or Telaprevir] Monotherapy with Peginterferon, Ribavirin, or a Direct Acting Antiviral Agent Treatment of Decompensated Cirrhosis with Peginterferon or Simeprevir *Patients who experienced nonresponse (partial or null) with Peginterferon plus Ribavirin therapy Source: AASLD/IDSA/IAS-USA ( Viewed April 8, 2014 AASLD/IDSA/IAS-USA 2014 HCV Treatment Recommendations Initial Therapy for Patients with Genotype 2 Chronic HCV Patients with GT 2 HCV: Initial Treatment & Retreatment of Relapsers* Recommended Therapy, Regardless of Eligibility for Interferon Therapy Sofosbuvir + Ribavirin x 12 weeks Alternative Therapy, Regardless of Eligibility for Interferon Therapy None Not Recommended Peginterferon + Ribavirin x 24 weeks Monotherapy with Peginterferon, Ribavirin, or a Direct Acting Antiviral Agent Any Regimen with Telaprevir, Boceprevir, or Simeprevir *Patients who experienced relapse after Peginterferon plus Ribavirin therapy Source: AASLD/IDSA/IAS-USA ( Viewed April 22, 2014 Hepatitis web study 8

9 AASLD/IDSA/IAS-USA 2014 HCV Treatment Recommendations Retreatment of Patients with Genotype 2 Chronic HCV Patients with GT 2 HCV: Retreatment of Prior Nonresponders* Recommended Therapy Sofosbuvir + Ribavirin x 12 weeks^ Alternative Therapy Sofosbuvir + Peginterferon + Ribavirin x 12 weeks Not Recommended Peginterferon+Ribavirin+/ +/- [Telaprevir, Boceprevir, or Simeprevir] Monotherapy with Peginterferon, Ribavirin, or a Direct Acting Antiviral Agent Treatment of Decompensated Cirrhosis with Peginterferon *Patients who experienced nonresponse (partial or null) with Peginterferon plus Ribavirin therapy ^Patients with cirrhosis may benefit by extension of therapy to 16 weeks Source: AASLD/IDSA/IAS-USA ( Viewed April 22, 2014 Hepatitis web study TREATMENT OF CHRONIC HEPATITIS C: GENOTYPE 3 Treatment-Naïve, Prior Relapsers and Non- Responders 9

10 AASLD/IDSA/IAS-USA 2014 HCV Treatment Recommendations Initial Therapy for Patients with Genotype 3 Chronic HCV Patients with GT 3 HCV: Initial Treatment & Retreatment of Relapsers* Recommended Therapy, Regardless of Eligibility for Interferon Therapy Sofosbuvir + Ribavirin x 24 weeks Alternative Therapy, Eligible for Interferon Therapy Sofosbuvir + Peginterferon + Ribavirin x 12 weeks Not Recommended Peginterferon+Ribavirinx weeks Monotherapy with Peginterferon, Ribavirin, or a Direct Acting Antiviral Agent Any Regimen with Telaprevir, Boceprevir, or Simeprevir *Patients who experienced relapse after Peginterferon plus Ribavirin therapy Source: AASLD/IDSA/IAS-USA ( Viewed April 22, 2014 AASLD/IDSA/IAS-USA 2014 HCV Treatment Recommendations Retreatment of Patients with Genotype 3 Chronic HCV Patients with GT 3 HCV: Retreatment of Prior Nonresponders* Recommended Therapy Sofosbuvir + Ribavirin x 24 weeks Alternative Therapy Sofosbuvir + Peginterferon + Ribavirin x 12 weeks Not Recommended Peginterferon + Ribavirin i i +/- [Boceprevir or Simeprevir i or Telaprevir] Monotherapy with Peginterferon, Ribavirin, or a Direct Acting Antiviral Agent Treatment of Decompensated Cirrhosis with Peginterferon *Patients who experienced nonresponse (partial or null) with Peginterferon plus Ribavirin therapy Source: AASLD/IDSA/IAS-USA ( Viewed April 22,

11 GT2 and GT 3: SVR by Genotype FISSION (TN) S VR12 (%) / 162/ 68/ 52/ 102/ 110/ SVR12 (%) P < / / / / 32 19/64 P < / 63 SVR12 (%) / /109 60/98 SOF + RBV 12 weeks Jacobson et al. N Engl J Med 2013, 368: , Lawitz et al., N Engl J Med 2013, 368: , Sofosbuvir + Ribavirin for Genotype 3 VALENCE: 24 weeks, n= SVR 12 (%) 62 86/92 12/13 87/100 28/45 No cirrhosis Cirrhosis No cirrhosis Cirrhosis Naïve Treatment-experienced Zeuzem S, et al. N Engl J Med. 2014;370:

12 Novel HCV Treatment Regimens in HCV treatment naïve and experienced patients Sofosbuvir + Simeprevir Daclastasvir+Sofosbuvir Sofosbuvir/Ledipasvir ABT450/r + Ombitasvir + Dasabuvir ± RBV MK MK8742 Daclatasvir + Asunaprevir Pill Burden in HCV Therapy Fixed Dose Combination Ledipasvir/Sofosbuvir MK-5172 and MK DAA Regimens 450r/Ombitasvir +Dasabuvir Simeprevir plus Sofosbuvir Daclatasvir and Sofosbuvir Asunaprevir+ Daclatasvir+BMS Ribavirin 5-6 pills a day 12

13 COSMOS: Simeprevir + Sofosbuvir ± RBV in Genotype 1 HCV: Phase 2a Study Design Week Arm 1 SMV + SOF + RBV Post-treatment follow-up Enrolment ratio 2:1:2:1 Arm 2 Arm 3 SMV + SOF + RBV SMV + SOF Post-treatment follow-up Post-treatment follow-up Arm 4 SMV + SOF Post-treatment follow-up Cohort 1: Prior null responders (METAVIR F0-F2) F2) Cohort 2: Treatment-naive and prior null responders (METAVIR F3-F4) SMV 150 mg QD + SOF 400 mg QD +/- RBV 1000/1200 mg/day QD, once daily; RBV, ribavirin; SMV, simeprevir; SOF, sofosbuvir; SVR, sustained virologic response; SVR4, sustained virologic response 4 weeks after planned treatment end; SVR12, sustained virologic response 12 weeks after planned treatment end. Jacobson I, et al. AASLD Abstract LB-3; Lawitz, et al. EASL Abstract 165. Combination of Sofosbuvir (NUC) and Simeprevir (Protease Inhibitor): COSMOS SVR12 (%) SMV + SOF + RBV Cohort 1 (F0-F2 Nulls): SVR12 SMV + SOF Cohort 2 (F3-F4 Naives/Nulls): SVR12 (N = 80, all arms) (N = 87, all arms) SVR12 (%) 20 19/24 14/15 26/27 13/14 28/30 16/16 25/27 13/ Wk Arms 12-Wk Arms 24-Wk Arms 12-Wk Arms Relapse in 3 pts in Cohort 1 and 3 pts in Cohort 2; all with GT 1a and 2 with Q80K polymorphism at BL AEs (anemia and indirect bilirubin increases) largely confined to RBV arms SVR in patients with GT 1a and Q80K+ = 88%-100% Jacobson I, et al. AASLD Abstract LB-3. Lawitz, et al. EASL Abstract

14 Combination of Daclatasvir ( NS5A inhibitor) and Sofosbuvir (NS5B Nucleotide Inhibitor) Patients Achieving SVR12 HCV RNA <LLOQ Patients, % 100% 100% 100% 100% a % A LI SOF, DCV SOF C DCV + SOF E DCV + SOF + RBV G DCV + SOF H DCV + SOF RBV 100% I DCV + SOF 95% b J DCV + SOF + SOF + RBV + RBV 24 Weeks Treatment Naïve 12 Weeks Treatment Naïve 24 Weeks PI Failures GT1a - 98% (129/132) GT1b - 100% (35/35) BMS Confidential For Internal Use Only Sulkowski et al. N Engl J Med. 2014;370: Combination of Daclatasvir ( NS5A inhibitor) and Sofosbuvir (NS5B Nucleotide Inhibitor) Patients Achieving SVR12 GT 2 and 3 Combined GT 2 and 3 Analyzed Separately HCV RNA <LLOQ Patients, % % B LI SOF, DCV + SOF 100% D DCV + SOF a 86% F DCV + SOF + RBV HCV RNA <LLOQ Patients, % % a 89% GT2 DCV + SOF ± RBV GT3 DCV + SOF ± RBV 24 Weeks Treatment Naïve 24 Weeks Treatment Naïve BMS Confidential For Internal Use Only Sulkowski et al. N Engl J Med. 2014;370:

15 Sofosbuvir (NUC) + Ledipasvir (NS5A) in G1 Insights on Treatment Duration and Role of Ribavirin ION-1 Treatment Naïve ~16% w/cirrhosis 0 Weeks N=214 SOF + LDV N=217 N=217 SOF + LDV + RBV SOF + LDV SVR 99% 97% 98% N=217 SOF + LDV + RBV 99% ION-2 Treatment Experienced ~20% w/cirrhosis N=109 N=111 N=109 SOF + LDV SOF + LDV + RBV SOF + LDV 94% 96% 99% N=111 SOF + LDV + RBV 99% Afdhal N et al. N Engl J Med. 2014;370: ; Afdhal N et al. N Engl J Med. 2014;370: Sofosbuvir (NUC) + Ledipasvir (NS5A) in Genotype 1: ION-2 Special Subgroups ION-2 N=22 SOF + LDV 86% Treatment Experienced Cirrhosis N=22 N=22 SOF + LDV + RBV SOF + LDV 82% 100% N=22 SOF + LDV + RBV 100% ION-2 Treatment Experienced PI Failures N=66 SOF + LDV 94% N=64 N=50 SOF + LDV + RBV SOF + LDV 97% 98% N=51 Afdhal N et al. N Engl J Med. 2014;370: SOF + LDV + RBV 100% 15

16 Sofosbuvir (NUC) + Ledipasvir (NS5A) in Genotype 1: Shorter Duration Is Possible 0 Weeks SVR ION-3 1 N=215 SOF + LDV 94% Treatment Naïve N=216 SOF + LDV + RBV 93% No cirrhosis N=216 SOF + LDV 95% ELECTRON* 2 Treatment Naïve No cirrhosis N=25 SOF+LDV+RBV 68% Treatment Duration >6 weeks is needed for this combination *The addition of third DAA could allow for shorter therapy 1. Kowdley KV et al. N Engl J Med. 2014;370(20): ; 2. Gane EJ et al. Gastroenterology. 2014;146: Results: Reasons For Not Achieving SVR GT 1 Treatment-Naïve (ION-3) 8 Weeks 12 Weeks Patients, n (%) LDV/SOF n=215 LDV/SOF + RBV n=216 LDV/SOF n=216 SVR (94) 201 (93) 206 (95) Breakthrough Relapse 11 (5) 9 (4) 3 (1) Lost to Follow-Up 2 (<1) 6 (3) 7 (3) Kowdley K, et al. 49th EASL; London, England; April 9-13, Abst. O

17 Study Design-Synergy Trial Sofosbuvir (nucleotide NS5B inhibitor) 400 mg / ledipasvir (NS5A inhibitor) 90 mg once daily GS-9669 (non-nucleoside NS5B inhibitor) 500 mg once daily GS-9451 (a protease/ NS3/4 inhibitor) 80 mg once daily Week Treatment naïve All stages fibrosis Sofosbuvir + Ledipasvir (n=20) SVR12 Treatment naïve Cirrhosis excluded Sofosbuvir + Ledipasvir i + GS (n=20) SVR12 Treatment naïve Cirrhosis excluded Sofosbuvir + Ledipasvir + GS (n=20) SVR12 48 weeks Treatment Response (ITT) 17

18 3 Direct Acting Antiviral Regimen The 3D regimen includes: Co-formulated dabt-450/r/ombitasvir /O i with Dasabuvir ABT-450, a NS3/4A protease inhibitor (identified by AbbVie and Enanta) Ritonavir (pharmacokinetic enhancer) Ombitasvir (ABT-267), a NS5A inhibitor Dasabuvir (ABT-333), a non-nucleoside NS5B polymerase inhibitor 1 Feld J, et al. N Engl J Med. 2014; published on-line. 2 Zeuzem S, et al. N Engl J Med. 2014; published on-line. ABT-450/r (PI) + ABT-267 (NS5A) + ABT-333 (NNI) + RBV SAPPHIRE and TURQUOISE SAPPHIRE-1 Treatment Naïve 0% w/cirrhosis 1 N=473 0 Weeks 12 ABT-450/r + ABT ABT RBV 24 SVR 96% SAPPHIRE-2 Treatment Experienced 0% w/cirrhosis 2 N=297 ABT-450/r + ABT ABT RBV 96% TURQUOISE-II Treatment Naïve/ Experienced 100% w/cirrhosis 3 N=208 N=172 ABT-450/r + ABT ABT RBV ABT-450/r + ABT ABT RBV 92% 96% ABT-450/r, ABT-450 with ritonavir 1. Feld JJ et al. N Engl J Med. 2014;370(17): ; 2. Zeuzem S et al. N Engl J Med. 2014:370: ; 3. Poordad F et al. N Engl J Med. 2014; 370(21):

19 AbbVie Regimen Phase 3 Clinical Development Program Study Patients Treatment Regimen SVR 12 97% AbbVie regimen* + RBV (n=88) PEARL-II GT1b treatment-experienced (85/88) (12 weeks) (N=179) 100% AbbVie regimen* only (n=91) (91/91) 99% AbbVie regimen* + RBV (n=210) PEARL-III GT1b treatment-naive (209/210) (12 weeks) (N=419) 99% AbbVie regimen* only (n=209) (207/209) 97% AbbVie regimen* + RBV (n=100) PEARL-IV GT1a treatment-naive (97/100) (12 weeks) (N=305) 90% AbbVie regimen* only (n=205) (185/205) GT1 treatment-naive 92% AbbVie regimen* + RBV, 12 weeks (n=208) TURQUOISE-II II and treatment-experiencedexperienced (191/208) (12 & 24 weeks) w/compensated cirrhosis 96% AbbVie regimen* + RBV, 24 weeks (n=172) (N=380) (165/172) SAPPHIRE-I GT1 treatment-naive 96% AbbVie regimen* + RBV (n=473) (12 weeks) (N=631) (455/473) SAPPHIRE-II GT1 treatment-experienced 96% AbbVie regimen* + RBV (n=297) (12 weeks) (N=394) (286/297) * AbbVie Regimen = ABT-450/r/Ombitasvir(150/100/25 mg QD) plus Dasabuvir (250 mg BID) SAPPHIRE-I: Placebo-Controlled Design (N=631) Double-Blind Treatment Period 3D + RBV (n=473) Open-Label Treatment Period 48-Week Follow-Up Placebo (n=158) 3D + RBV 48-Week Follow-Up Week 0 Week 12 Week 24 Week 60 Week 72 Pi Primary Analysis: SVR 12 Feld JJ et al. N Engl J Med. 2014;370(17):

20 SAPPHIRE-I: Adverse Events Occurring in >10% of Patients in Either Group Event, n (%) 3D + RBV (N=473) Placebo (N=158) P Value Any AE 414 (87.5) 116 (73.4) <0.05 Fatigue 164 (34.7) 45 (28.5) NS Headache 156 (33.0) 42 (26.6) NS Nausea 112 (23.7) 21 (13.3) <0.05 Pruritus 80 (16.9) 6 (3.8) <0.05 Insomnia 66 (14.0) 12 (7.6) <0.05 Diarrhea 65 (13.7) 11 (7.0) <0.05 Ath Asthenia 57 (12.1) 1) 6(38) (3.8) < Rash 51 (10.8) 9 (5.7) NS AEs were generally mild. Feld JJ et al. N Engl J Med. 2014;370(17): HALLMARK-DUAL (AI ): Study Design Day 1 Week 12 Week 24 Week 48 Treatment-naive n Randomizatio 2:1 DCV 60 mg QD + ASV 100 mg BID 24 weeks Follow up 24 weeks (N = 203) a DCV-PBO + ASV-PBO 12 Enter another study: STOP weeks (N = 102) DCV + ASV 24 weeks Nonresponder Ineligible/intolerant DCV + ASV 24 weeks (N = 205) DCV + ASV 24 weeks (N = 235) Follow up 24 weeks Follow up 24 weeks Patients infected with HCV genotype 1b Treatment-naive Nonresponders: prior null or partial response to pegifn/rbv Interferon-ineligible/intolerant (treatment-naive or -experienced) due to Depression Anemia/neutropenia Compensated advanced fibrosis/cirrhosis (F3/F4) with thrombocytopenia SVR 12 Kao JH, et al. 49th EASL; London, England; April 9-13, Abst. P

21 HALLMARK-DUEL: Virologic Response - SVR 12 SVR 12 (Percentage of patients) a a,b Treatment- t Nonresponders Ineligible/ ibl naive intolerant SVR 12 rates documented on or after post-treatment Week 12 Treatment-naive: 91% Nonresponders: 82% Ineligible/intolerant: 83% Kao JH, et al. 49th EASL; London, England; April 9-13, Abst. P1300. Study Design: MK-5172 (100 mg QD) + MK-8742 (50 mg QD) ± RBV in 253 Patients TN + Cirrho osis n=123 n = 31 n = 29 n = 32 n = 31 + RBV No RBV + RBV No RBV Follow-up Follow-up Follow-up Follow-up PR-Nulls ± Cirrh hosis n=130 n = 32 n = 33 n = 33 n = 32 + RBV No RBV + RBV No RBV Follow-up Follow-up Follow-up Follow-up D1 TW4 TW8 TW12 TW18 FU4 FU8 SVR12 Lawitz E, et al. 49th EASL; London, England; April 9-13, Abst. O61. SVR24 21

22 Efficacy of MK MK-8742 ± RBV in Treatment-Naïve Patients with Cirrhosis: 12 vs 18 Weeks * 30* Breakthrough Relapse Discontinuation TW4 TW12 FU4/8 *Excludes patients who have not yet reached the FU4 time point 12 week arms include 97% of FU8 results Lawitz E, et al. 49th EASL; London, England; April 9-13, Abst. O61. Treatment Options in the Future for HCV Other NS5B Nonnucleoside Polymerase Inhibitor ± RBV NS5A Inhibitor ± RBV 1. Treatment duration: 6,8,12 weeks 2. Genotype 1b vs 1a 3. Non-genotype 1 4. Cirrhosis NS5B Nucleotide Polymerase Inhibitor ± RBV Platform Issues that may dictate treatment Pangenotypic Protease Inhibitor ± RBV Interferon ± RBV 5. Race and ethnicity 6. IL28B status 7. Viral resistance 8. Cost 22

23 Treatment Options in the Future for HCV Other NS5B Nucleotide Polymerase Inhibitor ± RBV NS5A Inhibitor ± RBV Pangenotypic Protease Inhibitor ± RBV NS5B Nonnucleoside Polymerase Inhibitor ± RBV 1. Treatment duration: 6,8,12 weeks 2. Genotype 1b vs 1a 3. Non-genotype 1 4. Cirrhosis Platform Issues that may dictate treatment Interferon ± RBV 5. Race and ethnicity 6. IL28B status 7. Viral resistance 8. Cost Treatment Options in the Future for HCV NS5B Nucleotide Polymerase Inhibitor ± RBV NS5A Inhibitor ± RBV Other NS5B Nonnucleoside Polymerase Inhibitor ± RBV 1. Treatment duration: 6,8,12 weeks 2. Genotype 1b vs 1a 3. Non-genotype 1 4. Cirrhosis Pangenotypic Protease Inhibitor ± RBV Platform Issues that may dictate treatment Interferon ± RBV 5. Race and ethnicity 6. IL28B status 7. Viral resistance 8. Cost 23